1. Field of the Invention
The present invention is related to medical treatments involving the human brain and, more specifically without limitation, to real-time automated prediction/detection and non-pharmacological contingent, or closed-loop prevention/control or blockage of brain state changes using electrical or thermal signals either individually or simultaneously for detection or prediction of seizures or other changes in brain states; automated timely and safe delivery of cryogenic therapies; quantitative assessment of their efficacy and safety; and means for optimization thereof.
2. Discussion of the Related Art
Neuronal and, by extension, brain metabolic and electrical activity of poikilothermic and homeothermic animals are without exception temperature-dependent. Low temperatures (below 35xc2x0 C.) in homeotherms, and more specifically in humans, have an easily discernible effect on behavior and on an EEG, which is a reliable index of cortical electrical activity. At such temperatures, cerebral blood flow, oxygen and glucose consumption become depressed and, due to tight electro-metabolic coupling, so does neuronal function and its by-product, electrical activity. Brain cooling has a protective effect on the integrity of its tissue, a feature that has therapeutic applications.
For example, hypothermia minimizes damage in models of brain ischemia by decreasing both the metabolic demand of the brain tissue and the production of glutamate and dopamine, which under certain conditions can be excito-toxic. These effects make hypothermia well-suited for the treatment of neurological diseases that are characterized by the following:
1) absolute or relative, global or local neuronal hyper excitability, such as in epilepsy;
2) an imbalance in the degree of neuronal activity between/among structures which form part of a functional network, such as in Parkinson""s disease;
3) reduction in the supply of energy substrates, such as in stroke; and
4) activation/release of pathoclitic enzymes, such as in trauma, stroke, infection or prolonged/frequent seizures (status epilepticus).
Cooling can also be used for functional cortical localization or assessment of cognitive functions to assist in neurosurgical planning. Cryogenics has definite important advantages over electrical stimulation, the current standard for cortical localization, as follows:
a) cooling, unlike electrical stimulation (ES), does not precipitate seizures; and
b) unlike ES, which requires at least two stimulating electrodes and which has the potential to reach all structures between the electrodes and even those remote to them via existing neural pathways, the effects of cooling remain more localized and are more gradual than ES, thus providing more selective and interpretable information and also a higher therapeutic index.
Although cooling of brain tissue has been an object of several prior art approaches for various medical treatments, most of those approaches have been limited to cooling the most superficial layers of small cortical areas or in some cases just the scalp. Some other prior art approaches utilize cryogenic energy to ablate or destroy brain tissue. Cooling for the sole purpose of tissue ablation/destruction requires processing of very few, if any, input signals and parameter controls whereas reversible safe cooling of brain tissue for control of state changes such as seizure blockage, as taught by the present disclosure for seizure blockage purposes, is a highly time-sensitive task. For example, while methods for measuring tissue properties, such as thermal conductivity for the purpose of controlling the extent and degree of freezing, which is an irreversible destructive procedure, are disclosed in U.S. Pat. No. 6,190,378, that procedure is neither time-sensitive nor dependent on the detection of changes in electrical or thermal signals as required for seizure blockage using reversible cooling. No prior art reference appears to disclose seizure blockage as taught herein; references that border on such an application appear to have very limited usefulness or relevance for the medical applications disclosed herein. One prior art reference discloses means to block seizures through reversible cooling, namely U.S. Pat. No. 6,248,126 to Lesser et al, but has significant limitations, which make it highly unlikely that seizures can be blocked using such a device, even if the seizures originate from exposed gyri, designated by numeral 4 in FIG. 1, for the following reasons:
1) placement of the device of the ""126 patent over the most superficial cortical layer of exposed gyri as taught by the ""126 patent prevents timely cooling of deeper cortical layers (IV-VI) from where most seizures originate because (a) there are no means for attachment and, as a result, the cooling device floats over the cerebrospinal fluid and the fluid currents, through convection, carry cooling energy away from the target site thereby slowing down the rate at which tissue cooling can occur at the most superficial cortical layers; and (b) thermal diffusivity of brain tissue is such that rapid or timely cooling of deeper layers to block seizures can not take place; and
2) the majority of cortical gyri are not exposed, designated by numeral 5 in FIG. 1, and thus are not amenable to cooling using such a device.
Epilepsy affects about 2.7 million people in the United States and about 60 million worldwide. Approximately 30% of this population has pharmaco-resistant epilepsy, defined as at least one monthly seizure despite treatment with appropriate drugs at therapeutic concentrations. New therapies, which are both safe and effective, are required, given the existent, unmet need. Cooling of brain tissue is one such therapy with great potential as its effects are fully reversible and safe since the range of effective temperatures has no adverse effects on tissue viability or integrity and it is not known to precipitate or worsen seizures. While as early as 1974, it was shown that lowering the temperature of the midbrain prevents epileptiform activity, this therapeutic modality has received little attention due mainly to lack of suitable implantable devices and of interest in therapies other than pharmacological ones. Newly published evidence lends more support for an anti-seizure role for cooling of brain tissue. For example, U.S. Pat. No. 6,248,126 to Lesser et al discloses the use of a device based on the Peltier effect for cooling small areas of the cortical surface for seizure control. That device has important practical limitations, as described below, which translate into reduced efficacy and applicability. For example, that device does not provide a means to transfer heat (or cooling) in a timely manner from the surface to deeper neocortical regions from where seizures originate, which considerably limits efficacy since the delay in delivering therapy to critical regions allows the seizure to spread and gain intensity. This delay is explained by the fact that temperature gradients are steep and limit cooling to the immediate vicinity of the electrode, which necessitates that the cooling source be located as close to the target as possible for the therapy to be effective. Thermal diffusivity brain models reveal that lowering the temperature of a region located 5 mm from the cooling source, which is the average width of the cortex, from 37xc2x0 C. to 16xc2x0 C. takes approximately thirty seconds. Since placement of a Peltier device as taught by Lesser et al is on the cortical surface and the distance between that Peltier device and the seizure-generating cortical layers is about 5 mm, it is highly unlikely that they can be cooled down sufficiently timely to block seizures and prevent their spread. For any contingent therapy to be efficacious, it must reach the site of origin within five seconds of seizure onset. The ability to rapidly reach the seizure-generating tissue (epileptogenic region) is essential for the success of cryogenic therapy. Moreover, the device and approach of the ""126 patent do not have the means to monitor tissue electrical activity required to maximize efficacy, minimize the risk of freezing the tissue, assess therapeutic efficacy, and operate efficiently. Other prior art cooling catheters and probes are not suitable for use in epilepsy.
Cooling offers certain advantages over electrical stimulation for control of state changes or of cortical or subcortical functions as follows:
a) the only critical control parameter in cooling therapy is temperature as compared to intensity, frequency, pulse width, waveform, size and orientation of the field orientation, which determine efficacy and safety of electrical stimulation;
b) cooling has a greater safety margin than electrical stimulation because of the less instantaneous nature of the change in temperature particularly at the electrode-tissue interface, as opposed to charge deposition over the area covered by the electrical field and the known ability of electrical stimulation to induce seizures when certain parameters are utilized; and
c) cooling allows good-quality recording of electrical brain signals during cryogenic therapy for continuous real-time assessment of efficacy, an important function which can not be accomplished during delivery of electrical therapy, since electrical therapy saturates amplifiers and distorts brain electrical activity, not only for the duration of the electrical stimulation but also for a few seconds after its conclusion, which precludes meaningful analysis and valid interpretation of brain electrical signals. However, since electrical diffusivity is much higher than thermal diffusivity, electrical therapy may have quicker effects than is realizable from cryogenic therapy.
What is needed is a multi-purpose electrode, which the present invention provides for single, dual, simultaneous or sequential electrical and/or cryogenic therapy for control of brain state changes or of cortical and subcortical functions. What is also needed is a cooling device that is principally, but not only, activated in response to a cue including, but not limited to, detection or prediction of a seizure, to thereby minimize power consumption, a prerequisite for miniaturization and implantation.
The improvement of the multi-purpose electrode mechanism of the present invention for prediction or detection and control of changes in brain state includes a shaft portion structured for insertion into target tissue of the brain of a subject patient, cooling means configured to operatively apply cooling therapy to the target tissue, sensing means including at least one sensor monitoring a biological signal of the subject patient, control means responsive to the sensing means wherein the control means is structured to, in response to signals from the sensing means that indicate the occurrence of a change of state, automatically cause the cooling means to initiate or terminate the cooling therapy, and an energy source for powering the various components of the multi-purpose electrode mechanism.
The cooling means of the multi-purpose electrode mechanism includes at least one extendable element housed within the shaft portion and structured to be extended outwardly from the shaft portion into target tissue, either manually or by motor means. The at least one extendable element includes at least one cooling element, which may be hollow with a closed distal end and a dividing wall that extends from near the proximal end to near the distal end thereof that separates the at least one cooling element into side-by-side first and second channels with fluid flow communication between the first and second channels at the distal end thereof, or may be constructed of a solid material having high thermal conductivity. The cooling means also includes either a reservoir for containing coolant and pumping means structured to pump coolant to and from the reservoir and to the at least one cooling element, or a refrigerant source containing refrigerant at an elevated pressure, distribution means for distributing the refrigerant from the refrigerant source to the at least one cooling element, and means for removing the refrigerant from the cooling element or from the shaft portion.
The sensing means may include a sensor or sensors positioned in one or more of the extendable elements and may include one or more sensor mounted on the shaft portion to operatively contact target tissue adjacent thereto.
The multi-purpose electrode mechanism may also include stimulation means having at least one electrical contact structured to operatively apply electrical stimulation therapy to the target tissue wherein the control means, in response to signals from the sensing means that indicate the occurrence or presence of a change of state, is structured to automatically cause the stimulation means to initiate or terminate the electrical stimulation therapy.
The cooling means of multi-purpose electrode mechanism may include at least one thermoelectric device.
The sensing means and control means of the multi-purpose electrode mechanism may be structured to sense and control one-, two-, and/or three-dimensional configurations. The sensing means may be structured to sense chemical signals arising from ions, neurotransmitters and/or pH, and/or to sense physical signals arising from infrared, pressure and/or acoustics.
The principal objects and advantages of the present invention include: providing a multi-purpose electrode that can be used to detect relevant one-, two-, or three-dimensional changes in electrical or thermal or other types of signals reflective of brain state; providing such a multi-purpose electrode that can be used to control or prevent changes in brain state by, for example, lowering, in real-time, brain temperature at the cortex, white matter, or subcortical structures for one-, two-, or three-dimensional detection or treatment purposes; providing such a multi-purpose electrode that can be used to evaluate the efficacy of therapy in real time while the therapy is being delivered and optimize it; providing such a multi-purpose electrode that can provide electrical, thermal, or other feedback to a control system connected to the electrode; providing such a multi-purpose electrode that can be used to evaluate the safety of therapy in real time while the therapy is being delivered to thereby minimize the risk of injury to tissue being treated; providing such a multi-purpose electrode that can be used to detect and control in a timely fashion pathological changes in brain, spinal cord, spinal roots, or peripheral nerves of states such as stroke, trauma, depression, pain movement disorders, cognitive functions, behavior or emotions or physiological ones, such as changes in level of attention, drowsiness, and others; providing such a multi-purpose electrode that may be used to effect cooling of brain tissue in response to changes in signals other than electrical or thermal, which may occur prior to or at the onset of changes in brain state, such as signals arising from cardiovascular, autonomic, chemical (pH, [Ca++], [K+], amino acids, energy substrates, catabolic products, free radicals, etc.) or physical (pressure, sound, optical, etc.) phenomena; and generally providing such a multi-purpose electrode that is reliable in performance, capable of long lasting life, and particularly well-adapted for the proposed usages thereof.
Other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings wherein are set forth, by way of illustration and example, certain embodiments of this invention.